Acid sphingomyelinase inhibition results in profound rescue of neuronal function in glucocerebrosidase deficiency – unexpected opposing effects of Parkinson disease risk genes

The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. Variants in the two lysosomal disease genes () and () are genetic risk factors for sporadic Parkinson’s disease (PD). We investigated the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency in zebrafish (), an ideally suited vertebrate model system to study gene-gene interaction. Combined genetic inactivation of GCase and ASM resulted in marked synergistic increases of key sphingolipids in the ; double-mutant compared to or single mutant zebrafish. However, the ; double-mutant zebrafish unexpectedly displayed a complete reciprocal rescue of mitochondrial respiratory chain function compared to the or single mutant zebrafish. The mitochondrial rescue effect resulted in abolished lipid membrane peroxidation, normalisation of motor behaviour and prolonged survival in the ; double-mutant zebrafish compared to the single mutant zebrafish strain. RNAseq-based transcriptomic pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. Complementing experiments in a previously established model of GCase deficiency in dopaminergic SH-SY5Y cells demonstrated that the observed rescue effect is autophagy-independent. Our study highlights the importance of a functional validation for any putative interactions between PD risk genes and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.